11-18335723-A-G

Variant names:

• chr11-18335723-A-G
• rs4150581
• NM_005316.4:c.155-31A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005316.4(GTF2H1):​c.155-31A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,524,534 control chromosomes in the GnomAD database, including 216,994 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.42 (15570 hom., cov: 33)
  • Exomes 𝑓: 0.53 (201424 hom.)
• Consequence: GTF2H1 NM_005316.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• Publications: 34 publications found

Genes affected

GTF2H1 (HGNC:4655): (general transcription factor IIH subunit 1) Enables thyroid hormone receptor binding activity. Involved in positive regulation of transcription, DNA-templated and transcription by RNA polymerase II. Located in nucleoplasm. Part of transcription factor TFIIH core complex and transcription factor TFIIH holo complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2H1	NM_005316.4	c.155-31A>G		intron_variant	Intron 2 of 14	ENST00000265963.9	NP_005307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2H1	ENST00000265963.9	c.155-31A>G		intron_variant	Intron 2 of 14	1	NM_005316.4	ENSP00000265963.4

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63521 AN: 152030 Hom.: 15570 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.406

GnomAD2 exomes AF: 0.477 AC: 115961 AN: 242932 AF XY: 0.478

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.372

Gnomad EAS exome AF: 0.573

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.527

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.533 AC: 731530 AN: 1372384 Hom.: 201424 Cov.: 20 AF XY: 0.528 AC XY: 362459 AN XY: 686998

African (AFR) AF: 0.129 AC: 4068 AN: 31512

American (AMR) AF: 0.500 AC: 21408 AN: 42774

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 9210 AN: 24780

East Asian (EAS) AF: 0.566 AC: 22231 AN: 39250

South Asian (SAS) AF: 0.386 AC: 32139 AN: 83182

European-Finnish (FIN) AF: 0.526 AC: 27860 AN: 52992

Middle Eastern (MID) AF: 0.293 AC: 1617 AN: 5516

European-Non Finnish (NFE) AF: 0.565 AC: 584585 AN: 1035128

Other (OTH) AF: 0.496 AC: 28412 AN: 57250

GnomAD4 genome AF: 0.418 AC: 63533 AN: 152150 Hom.: 15570 Cov.: 33 AF XY: 0.418 AC XY: 31080 AN XY: 74356

African (AFR) AF: 0.150 AC: 6230 AN: 41542

American (AMR) AF: 0.482 AC: 7369 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1275 AN: 3472

East Asian (EAS) AF: 0.587 AC: 3034 AN: 5166

South Asian (SAS) AF: 0.404 AC: 1946 AN: 4820

European-Finnish (FIN) AF: 0.517 AC: 5460 AN: 10560

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36681 AN: 67992

Other (OTH) AF: 0.405 AC: 854 AN: 2108

Alfa AF: 0.494 Hom.: 38972

Bravo AF: 0.405

Asia WGS AF: 0.456 AC: 1584 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.0
DANN	Benign	0.64
PhyloP100		0.17
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4150581; hg19: chr11-18357270; COSMIC: COSV107230250; COSMIC: COSV107230250;